Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bacterial enterotoxin superantigens bind directly to HLA class II molecules (HLA-DR) expressed on both APC and activated human T cells, and simultaneously bind to certain V beta chains of the TCR. In this report, we compared early T cell signaling events in human alloantigen-stimulated T cells when activated by HLA-DR ligation through antibody cross-linking or by direct enterotoxin superantigen binding. Both types of stimuli induced tyrosine phosphorylation of phosphatidylinositol-specific phospholipase C gamma 1 (PLC gamma 1) and an increase in intracellular calcium concentration; however, superantigen-induced signaling was stronger than class II ligation alone. Antibody-mediated ligation of HLA-DR with CD3 resulted in augmented PLC gamma 1 activation and increased calcium mobilization, consistent with a mechanism of superantigen activity through a combination of class II and CD3/Ti signals. In addition, down-modulation of CD3 receptors with antibody demonstrated that superantigen-induced signaling events were CD3-dependent. Superantigen signaling was also class II-dependent, in that resting T cells were not responsive to direct enterotoxin stimulation. To address how early signal transducing activity correlated with T cell responsiveness, alloantigen-primed T cells were activated with immobilized class II-specific mAb or soluble superantigen. Both HLA-DR mAb-stimulated T cells and enterotoxin-treated T cells proliferated strongly in response to co-stimulation by a combination of CD28 receptor engagement and PMA addition. In addition, superantigen-induced growth was induced by CD28 receptor ligation with antibody or the B7 counter-receptor expressed on Chinese hamster ovary cells. Taken together, these results indicate that class II molecules expressed on activated T cells are directly coupled to the PLC gamma 1 signal transduction pathway, and that coligation of HLA-DR with CD3 augments T cell signaling comparable to that induced by enterotoxin superantigen. Thus, we suggest that superantigen-induced early signaling responses in activated T cells may be due in part to class II transmembrane signals induced when HLA-DR and V beta are ligated in cis.
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PMID:Superantigen and HLA-DR ligation induce phospholipase-C gamma 1 activation in class II+ T cells. 138 26

In order to elucidate the role of HLA class II molecules in generation of self-nonself discrimination of human T cells, we have analyzed T cell functions in an HLA class II-negative severe combined immunodeficiency patient. Patient PBL expressed no HLA-DR, -DQ, and -DP antigens as judged by immunofluorescence using mAb, and failed to elicit MLR responses from unrelated controls. Patient PBL contained mature T cells (CD3+ TCR alpha beta+) of the CD4 and CD8 subset, showing an apparently normal TCR diversity, as judged by use of anti-V beta 5, -V beta 6, -V beta 8, -V beta 12, and -V alpha 2 mAb. Patient PBL proliferated in response to anti-TCR/CD3 mAb and PHA, but not against recall Ag, despite immunization, and mounted proliferative, but not cytotoxic, responses against allogeneic cells. To find out whether the MLR responses were a consequence of self-nonself discrimination, the patient HLA-DR and -DQ genotype was determined using sequence specific oligonucleotide probes, revealing DRB1*0401 DQB1*0301 alleles, and MLR were set up against a panel of HLA-DR4 DQw3 stimulators matched or mismatched for DRB1*0401 DQB1*0301. Results showed no MLR against DRB1*0401 DQB1*0301 stimulators, but significant responses against stimulators expressing DRB1*0408 and/or DQB1*0302 alleles. Moreover, the DRB1*0401 DQB1*0301 APC reconstituted proliferation of patient PBL against PPD; this response was completely blocked by an anti-IL-2R (p55) mAb and partially also by anti-HLA-DR and -DQ mAb, indicating recognition of these molecules as restriction element presenting Ag--i.e., as self--by patient T cells. In conclusion, the novel demonstration of self-nonself discrimination by T cells from an HLA class II-negative SCID patient suggests that it may not be absolutely dependent on regular HLA class II expression within the differentiation environment in humans.
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PMID:Allorecognition and T cell repertoire selection in severe combined immunodeficiency lacking HLA class II antigens. 153 39

Staphylococcal enterotoxins (SE) are known to stimulate a large proportion of T cells. SE bind to MHC-class II molecules on APC and a particular segment of certain TCR V beta and V gamma gene products. Resting human T cells do not express HLA class II Ag and therefore cannot present SE to T cells. Activated human T cells, however, do express HLA-DR, -DP, and -DQ Ag and could consequently serve as APC for SE. As such, local immune responses to SE might be regulated and/or abrogated by SE-mediated T-T cell interactions leading to T cell destruction. We have investigated if such SE-mediated T-T cell interactions can occur in vitro using human cytolytic TCR-alpha beta+ and TCR-gamma delta+ T cell clones. We demonstrate that the TCR-alpha beta+ T cell clones can efficiently present staphylococcal enterotoxin A (SEA) to each other: T cell clones coated with SEA are lysed by SEA-reactive T cell clones but not by a SEA-nonreactive T cell clone. Furthermore, the SEA-reactive TCR-alpha beta+ clones (but not the SEA-nonreactive clone) destruct themselves in the presence of SEA at low concentrations of SEA (less than 0.01 microgram/ml). Also, SEA-coated T cell clones can induce proliferative responses although such responses are much weaker than those induced when B cells are used as stimulator cells. In contrast, the SEA-reactive TCR-gamma delta+ T cell clones are resistant to autokilling in the presence of SEA and they do not lyse SEA-coated TCR-gamma delta+ targets. However, such targets can be lysed by TCR-alpha beta+ effector cells. These results indicate that TCR-gamma delta+ cells are relatively resistant to lysis and that during local nonspecific immune responses triggered by SE, which induces HLA-class II expression by the responding T cells, SE-mediated T-T cell interactions may play a role in the regulation and/or abrogation of these immune responses.
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PMID:Staphylococcal enterotoxin-mediated human T-T cell interactions. 153 87

We have found that the low immune response to streptococcal cell wall Ag (SCW) was inherited as a dominant trait and was linked to HLA, as deduced from family analysis. In the present report, HLA class II alleles of healthy donors were determined by serology and DNA typing to identify the HLA alleles controlling low or high immune responses to SCW. HLA-DR2-DQA1*0102-DQB1*0602(DQw6)-Dw2 haplotype or HLA-DR2-DQA1*0103-DQB1*0601(DQw6)-DW12 haplotype was increased in frequency in the low responders and the frequency of HLA-DR4-DRw53-DQA1*0301-DQB1*0401(DQw4)-Dw15 haplotype or HLA-DR9-DRw53-DQA1*0301-DQB1*0303(DQw3)-Dw23 haplotype was increased in the high responders to SCW. Homozygotes of either DQA1*0102 or DQA1*0103 exhibited a low responsiveness to SCW and those of DQA1*0301 were high responders. The heterozygotes of DQA1*0102 or 0103 and DQA1*0301 showed a low response to SCW, thereby confirming that the HLA-linked gene controls the low response to SCW, as a dominant trait. Using mouse L cell transfectants expressing a single class II molecule as the APC, we found that DQw6(DQA1*0103 DQB1*0601) from the low responder haplotype (DR2-DQA1*0103-DQB1*0601(DQw6)-Dw12) activated SCW-specific T cell lines whereas DQw4(DQA1*0301 DQB1*0401) from the high responder haplotype (DR4-DRw53-DQA1*0301-DQB1*0401(DQw4)-Dw15) did not activate T cell lines specific to SCW. However, DR4 and DR2 presented SCW to CD4+ T cells in both the high and low responders to SCW, hence the DR molecule even from the low responder haplotype functions as an restriction molecule in the low responders. Putative mechanisms linked to the association between the existence of DQ-restricted CD4+ T cells specific to SCW, and low responsiveness to SCW are discussed.
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PMID:HLA-DQ-restricted CD4+ T cells specific to streptococcal antigen present in low but not in high responders. 167 41

The homology of class I major histocompatibility complex (MHC) antigens, class II MHC antigens, and immunoglobulin molecules has suggested their divergence from a common ancestral gene. We report here a monoclonal antibody (mAb), PAC.M1, which reacts with HLA class I heavy chains, HLA class II alpha and beta chains, and the light chain of human immunoglobulin by Western blot analysis. PAC.M1 reacted with 44 kd, 33 kd, and 29 kd species when tested on membrane glycoproteins from TRal, a B-lymphoblastoid cell line (B-LCL). Two-dimensional electrophoresis and Western blotting of TRal glycoproteins showed that these species had the appropriate electrophoretic mobilities for class I heavy chain and class II alpha and beta subunits. The presence of the epitope was verified on class II alpha and beta subunits by Western blotting of purified alpha beta-invariant chain complexes, and on class I heavy chains by Western blotting of purified class I antigens. The PAC.M1 mAb also reacted with immunoglobulin light chains when Western blotting was performed with normal human serum and purified IgG and IgM as antigens. While reactivity of the mAb with beta-2 microglobulin (beta 2m) was difficult to detect by Western blotting, binding of PAC.M1 to purified beta 2m was detectable in a solid-phase binding assay. Thus, PAC.M1 reacts with a determinant shared by a number of members of the immunoglobulin superfamily.
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PMID:An epitope common to HLA class I and class II antigens, Ig light chains, and beta 2-microglobulin. 243 22

PBMC from healthy adult individuals seropositive for measles virus (MV) were tested for their capacity to proliferate to UV-inactivated MV (UV-MV) or to autologous MV-infected EBV-transformed B cell lines (EBV-BC). MV-specific T cell responses were observed in 11 of 15 donors tested (stimulation index greater than 2), when optimal doses of UV-MV were used in proliferative assays. T cell clones were generated from PBMC of three donors responding to MV, by using either UV-MV or MV-infected autologous EBV-BC as APC. Stimulation with UV-MV generated exclusively CD3+ CD4+ CD8- MV-specific T cells, whereas after stimulation of PBMC with MV-infected EBV-BC, both CD3+ CD4+ CD8- and CD3+ CD4- CD8+ MV-specific T cell clones were obtained. Of 19 CD4+ T cell clones tested so far, 7 clones reacted specifically with purified fusion protein and 1 with purified hemagglutinin protein. Seven clones proliferated in response to the internal proteins of MV. Three clones reacted to whole virus but not to one of the purified proteins, whereas one clone seemed to recognize more than one polypeptide. Some of the T cell clones, generated from in vitro stimulation of PBMC with UV-MV, failed to recognize MV Ag when MV-infected EBV-BC were used as APC instead of UV-MV and PBMC. CD3+ CD4+ CD8- T cell clones recognized MV in association with HLA class II Ag (HLA-DQ or -DR), and most of them displayed CTL activity to autologous MV-infected EBV-BC. All CD4+ HLA class II-restricted CTL clones thus far tested were capable of assisting B lymphocytes for the production of MV-specific antibody. The CD4- CD8+ T cell clone MARO 1 recognized MV in association with HLA class I molecules and displayed cytotoxic activity toward MV-infected EBV-BC.
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PMID:Measles virus-specific human T cell clones. Characterization of specificity and function of CD4+ helper/cytotoxic and CD8+ cytotoxic T cell clones. 246 43

The relative ability of unmanipulated monocytes, B cells, and dendritic cells (DC) from peripheral blood to stimulate an allogeneic MLR has not been clearly established. We studied the allostimulatory ability of these cell types from minimally manipulated PBMC populations to exclude the induction of stimulatory properties by the complex isolation procedures commonly used to isolate blood DC. Highly purified cell populations were obtained from volunteer donors by immunolabeling PBMC with mAb directed against known lineage-associated markers and separating the positive and negative population on a FACS. These cells were used as stimulators in an allogeneic MLR. The major allostimulatory activity resides in the CD14, CD11b, and CD19 negative fractions. A mixture of antibodies to T, B, NK, monocyte, and FcRIII positive cells was then used to isolate a minor cell population that contained a markedly superstimulatory population of (CD3, CD14, CD16, CD19, and CD57) negative cells. We demonstrate that this activity is constitutive, and is not an artifact of the adherence and in vitro culture steps used in conventional DC purification procedures. We also show by rigorous depletion of the T cell responders that endogenous HLA class II positive cells in the responder population have little role in presenting processed allogeneic antigens during the primary MLR. Monocytes and B cells are stimulators of the allogeneic MLR, but are considerably less potent on a cell for cell basis than the putative DC population. Finally, because human blood and tonsil DC lack detectable CD43 by immunoperoxidase staining, in contrast to monocytes and activated B cells, we examined the ability of CD43 negative and positive cells to stimulate an allogeneic MLR. Similar allostimulatory activity for the human MLR was shown to reside in both the CD43 positive and negative fractions, suggesting that there may be some heterogeneity in the APC population.
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PMID:Allostimulatory cells in fresh human blood: heterogeneity in antigen-presenting cell populations. 769 38

The behavior of mouse I-Ak molecules was studied in the human Ag presentation mutants T2 and 9.5.3, which contain deleted or mutated HLA DM genes. HLA class II molecules expressed by these APC are defective in presentation of native Ag and are mostly complexed with class II-associated invariant chain peptides (CLIP). In contrast to human class II molecules, a significant proportion of mouse I-Ak molecules expressed in T2 and 9.5.3 were associated with antigenic peptides, indicating that I-Ak/peptide assembly is possible in the absence of the Dm proteins. Thus, the presentation of determinants derived from hen egg lysozyme (HEL), keyhole limpet hemocyanin, and conalbumin was normal in 9.5.3Ak and a conalbumin determinant was presented normally by T2.Ak. However, the keyhole limpet hemocyanin determinant was not presented by T2.Ak, and HEL46-61 was only presented at a low level by these APC. SDS-stable, dimeric I-Ak molecules were expressed by both T2.Ak and 9.5.3Ak and formed late in their intracellular transport. Presentation of HEL46-61 was partially inhibited by disrupting vacuolar acidification in 9.5.3Ak, consistent with I-Ak/peptide assembly in a post-Golgi endosomal compartment. Accordingly, Dm is not an obligatory requirement for MHC class II/peptide assembly. We propose that Dm influences the displacement of CLIP from recently synthesized class II molecules, a process that is likely to be less critical for I-Ak because of its low affinity for CLIP.
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PMID:Antigen presentation and assembly by mouse I-Ak class II molecules in human APC containing deleted or mutated HLA DM genes. 798 44

Our recent study indicated that all the insulin autoimmune syndrome (IAS) patients had specific HLA class II alleles, the DRB1*0406, DQA1*0301, and DQB1*0302, which allowed T cells to proliferate when autologous APC were exposed to human insulin. The study implied that gene products of DRB1*0406, DQA1*0301, and/or DQB1*0302 may be involved in the presentation of human insulin to T cells. We therefore examined T cell response of healthy donors with different HLA phenotypes to human insulin using an autologous MLR system. The T cells from not only IAS patients but also healthy donors were able to proliferate after exposure of human insulin to autologous APC with DRB1*0406, DQA1*0301, and DQB1*0302 products. The class II molecules are considered to be involved in the recognition of human insulin by T cells. The proliferative response of T cells was completely blocked by anti-HLA-DR mAb and not by anti-HLA-DQ mAb or other mAb. Furthermore, human insulin-specific CD4-positive T cell clones were established from blast cells in autologous MLR of PBMC from two healthy donors with DRB1*0406 in the presence of human insulin. Using DRB1*0406-transfected L cells as APC, we confirmed that these T cells clones recognize human insulin in the context of gene products of DRB1*0406. These results provide the first evidence that HLA-DRB1*0406 products act as the dominant restriction element for the presentation of human insulin to T cells, and suggest that this particular class II gene, HLA-DRB1*0406, contributes to the development of IAS.
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PMID:Recognition of human insulin in the context of HLA-DRB1*0406 products by T cells of insulin autoimmune syndrome patients and healthy donors. 822 61

Superantigens interact with specific V beta elements of the T cell receptor and consequently activate all T cells bearing those elements. The ability of superantigens to stimulate T cells depends on the presence of APC that express MHC class II molecules on their surface. The question we are addressing is: do superantigens have to be seen in context of MHC class II molecules, or can they be recognized directly by T cell-receptor elements? We have previously shown that the APC requirement for the stimulation of T cells by the streptococcal superantigen, pep M5, can be bypassed by the addition of PMA and cytokines or by crosslinking CD28 molecules. Here we asked if the response of APC-depleted T cells to this superantigen is V beta-restricted and whether in the presence of PMA and cytokines the specificity of pep M5 to V beta elements is altered. We provide evidence that in the absence of APC, but in the presence of PMA and cytokines, the specificity of pep M5 to V beta elements is identical to that observed when APC are present, with V beta 2, V beta 4, and V beta 8 being significantly expanded. In addition, we ruled out the possibility that the response is due to a minor contamination with APC or to the expression of DR molecules on T cells because anti-HLA class II monoclonal antibodies did not block the reconstituted response, whereas they totally abrogated the response in the presence of APC. We conclude that pep M5 does not have to complex with MHC class II molecules in order to interact with specific V beta elements. In addition, we propose that the inhibitory effects of the anti-class II antibodies when APC are present may be due to preventing pep M5 from binding and activating APC, thereby blocking the production of costimulatory molecules necessary for T cell activation by this superantigen.
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PMID:Preservation of the specificity of superantigen to T cell receptor V beta elements in the absence of MHC class II molecules. 825 43


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